磷脂酶 D2 依赖性环磷酸脂酸对核激素受体 PPARγ的抑制作用。
Phospholipase D2-dependent inhibition of the nuclear hormone receptor PPARgamma by cyclic phosphatidic acid.
机构信息
Department of Physiology, University of Tennessee Health Science Center Memphis, Memphis, TN 38163, USA.
出版信息
Mol Cell. 2010 Aug 13;39(3):421-32. doi: 10.1016/j.molcel.2010.07.022.
Abstract
Cyclic phosphatidic acid (1-acyl-2,3-cyclic-glycerophosphate, CPA), one of nature's simplest phospholipids, is found in cells from slime mold to humans and has a largely unknown function. We find here that CPA is generated in mammalian cells in a stimulus-coupled manner by phospholipase D2 (PLD2) and binds to and inhibits the nuclear hormone receptor PPARgamma with nanomolar affinity and high specificity through stabilizing its interaction with the corepressor SMRT. CPA production inhibits the PPARgamma target-gene transcription that normally drives adipocytic differentiation of 3T3-L1 cells, lipid accumulation in RAW264.7 cells and primary mouse macrophages, and arterial wall remodeling in a rat model in vivo. Inhibition of PLD2 by shRNA, a dominant-negative mutant, or a small molecule inhibitor blocks CPA production and relieves PPARgamma inhibition. We conclude that CPA is a second messenger and a physiological inhibitor of PPARgamma, revealing that PPARgamma is regulated by endogenous agonists as well as by antagonists.
摘要
环状磷酸脂酸（1-酰基-2,3-环甘油磷酸酯，CPA）是自然界最简单的磷脂之一，存在于从黏菌到人类的细胞中，但其功能尚不清楚。我们发现，在哺乳动物细胞中，CPA 通过磷脂酶 D2（PLD2）以刺激偶联的方式生成，与核激素受体 PPARγ以纳摩尔亲和力和高特异性结合，并通过稳定其与核心抑制因子 SMRT 的相互作用来抑制其功能。CPA 的产生抑制了通常驱动 3T3-L1 细胞脂肪分化、RAW264.7 细胞和原代小鼠巨噬细胞中脂质积累以及体内大鼠模型中动脉壁重塑的 PPARγ 靶基因转录。通过 shRNA、显性负突变体或小分子抑制剂抑制 PLD2 可阻断 CPA 的产生并解除对 PPARγ 的抑制。我们的结论是，CPA 是一种第二信使和 PPARγ 的生理抑制剂，这表明 PPARγ 受到内源性激动剂和拮抗剂的调节。
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